Camptothecin is an alkaloid isolated by Wall et al. (J. Am. Chem. Soc., 88, 3888-3890 (1966)) for the first time from the tree Camptotheca acuminata, a plant native to China, belonging to the Nyssaceae family.
The molecule consists of a pentacyclic structure with a lactone in the E ring, which is essential for cytotoxicity.
For a review of the camptothecins and the problems relating to their use as medicaments, as well as the resolution of a number of such problems, see European Patent EP 1044977, filed in the name of the applicants. Among the preferred compounds of this latter patent we should mention 7-tert-butoxyiminomethyl-camptothecin, which is active orally. Said compound, endowed with substantial activity, cannot be formulated in aqueous liquid compositions, particularly those suitable for the injectable administration route. The problem of the solubility of the camptothecins is well known to experts in the field.
Soluble camptothecin prodrugs are disclosed in U.S. Pat. No. 4,943,579, published on 24 Jul. 1990, which provides esters in position 20 of camptothecins with amino acids directly bound to the hydroxyl of the lactone ring. As discussed in this reference, the problem of making camptothecin and its hydrosoluble derivatives is rendered more difficult by the fact that it is not possible to alter the lactone ring without a loss of therapeutic activity. At the same time, there is, in any event, the problem of reducing the typical toxicity of the camptothecins, particularly at intestinal level. WO 97/21865, The Stehlin Foundation, published on 7 Aug. 1997, provides camptothecin prodrugs for the purposes of prolonging the stability of the lactone ring, which is hydrolysed in vivo, giving rise to an inactive toxic metabolite. To this end, the hydroxy group of the lactone ring is esterified with carboxylic acids of varying length, optionally bearing an epoxide group in the chain. The compounds described in this reference are more liposoluble and are therefore going in a different direction as compared to the present invention. Conover C. D., et al., Anti-Cancer Drug Design (1999), 14, 499-506 describe a camptothecin-polyethylene glycol hydrosoluble macromolecular transport system, in which various spacers of an amino acid nature affect its pharmacokinetic and anticancer activity characteristics. WO 00/08033, The University of Kansas, published on 17 Feb. 2000, describes hydrosoluble prodrugs with a sterically hindered hydroxy group, which is esterified with a phosphono-oxymethyl group. Singer J. W., et al., Journal of Controlled Release, 74 (2001), 243-247, describe hydrosoluble conjugates of camptothecin with polyglutamic acid-glycine. Matsumoto H., et al., Bioorganic & Medicinal Chemistry Letters 11 (2001), 605-609 describe hydrosoluble prodrugs of an HIV virus protease inhibitor (molecule of a dipeptide nature, differing enormously from the molecular structure of camptothecin) and to that end functionalise a hydroxyl group with a portion formed by a spacer part and a solubilising part. The spacer part is provided by a bicarboxylic acid, whereas the solubilising part is provided by a diamine. WO 01/09139, The Stehlin Foundation, published on 8 Feb. 2001, describes aryl esters of camptothecin in position 20, but does not address the problem of hydrosolubility, but rather that of the toxicity and prolonged stability of the lactone ring.
However, much in the design of new drugs various problems are encountered of a physicochemical nature, such as the stability of the molecule in plasma or its hydrosolubility for formulatory purposes, there is a constant search for a better therapeutic index.